Results from a preplanned interim analysis of the phase III iNNOVATE (PCYC-1127) study evaluating the investigational use of ibrutinib (Imbruvica) in combination with rituximab (Rituxan) in relapsed/refractory and treatment-naive patients with Waldenström’s macroglobulinemia were presented at the 2018 ASCO Annual Meeting (Abstract 8003) and were simultaneously published in The New England Journal of Medicine. The study met its primary endpoint for a clinically and statistically significant difference in progression-free survival (PFS) for patients treated with ibrutinib plus rituximab vs those who received placebo plus rituximab. Ibrutinib plus rituximab significantly reduced the risk of disease progression or death by 80% compared to placebo plus rituximab (hazard ratio [HR] = 0.20; confidence interval [CI] = 0.11–0.38, P < .0001). Furthermore, secondary endpoints including the response rate, time to next treatment, rate of sustained hemoglobin improvement, and number of participants with adverse events (AEs) support the primary endpoint.
In late 2017, the Independent Data Monitoring Committee recommended unblinding iNNOVATE based on these results. In addition, a supplemental New Drug Application was submitted to the US Food and Drug Administration (FDA) based on this data to expand the use of ibrutinib as a combination therapy in Waldenström’s macroglobulinemia.
“These important data demonstrate that ibrutinib plus rituximab resulted in marked improvement in progression-free survival across all lines of therapy in Waldenström’s macroglobulinemia regardless of patient subtypes, compared to placebo plus rituximab,” said Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and lead iNNOVATE study investigator. “Not only was there marked statistical and clinical difference in the efficacy compared to rituximab monotherapy, but the combination of ibrutinib and rituximab did not result in any unanticipated safety signals.”
Waldenström’s macroglobulinemia is a rare, slow-growing and incurable form of non-Hodgkin lymphoma with limited treatment options. WM typically affects older adults and is primarily found in the bone marrow, although lymph nodes and the spleen also may be affected. In January 2015, ibrutinib received FDA approval as monotherapy in Waldenström’s macroglobulinemia and is the first and only FDA-approved therapy specifically indicated for this disease.
More on iNNOVATE
The iNNOVATE study evaluated relapsed/refractory and treatment-naive Waldenström’s macroglobulinemia patients (n = 150) who were randomized to receive intravenous rituximab 375 mg/m2 once weekly for 4 consecutive weeks, followed by a second once-weekly for 4 consecutive weeks rituximab course after a 3-month interval. All patients received either ibrutinib 420 mg or placebo once daily continuously until disease progression or unacceptable toxicity. The primary endpoint was IRC-assessed PFS, and secondary objectives included overall response rate, hematological improvement measured by hemoglobin, median time to next treatment, overall survival (OS), and number of participants with AEs as a measure of safety and tolerability within each treatment arm.
With a median follow-up of 26.5 months, ibrutinib plus rituximab improved PFS compared with placebo plus rituximab (median PFS, not reached vs 20.3 months; HR = 0.20; CI = 0.11–0.38, P < .0001), with PFS rates of 82% vs 28% at 30 months, respectively. Notably, ibrutinib plus rituximab prolonged PFS in all relevant subgroups, including treatment-naive (HR = 0.34; CI = 0.12–0.95), relapsed (HR, 0.17; CI: 0.08–0.36), and in patients with MYD88 L265P and CXCR4 WHIM mutations (HR = 0.24; CI = 0.09–0.66) vs rituximab.
Overall response rates and major response rates were significantly higher for ibrutinib plus rituximab vs placebo plus rituximab (92% vs 47%; 72% vs 32% [both P < .0001]). In addition, there was an improvement in hemoglobin seen in patients treated with the combination vs the placebo plus rituximab arm (73% vs 41%, P < .0001).
Of the patients on ibrutinib plus rituximab, 75% continued on treatment at the time of analysis. Time to next treatment was not reached for ibrutinib plus rituximab and 18 months for placebo plus rituximab (HR = 0.096; P < .0001). The 30-month OS rates were 94% vs 92% in the two arms.
At the median time on treatment (ibrutinib plus rituximab, 25.8 months; rituximab plus placebo, 15.5 months), grade 3 or higher treatment-emergent AEs occurred in 60% of patients treated with ibrutinib plus rituximab vs 61% of patients treated with placebo plus rituxmab. Serious AEs occurred in 43% vs 33% of patients on ibrutinib plus ritxuimab compared to placebo plus rituximab. No fatal AEs occurred in the ibrutinib plus rituximab arm. Three fatal AEs occurred in the placebo plus rituximab arm. Meaningful reductions in any grade immunoglobin M flare (8% vs 47%) and grade 3 or higher infusion reactions were observed (1% vs 16%) with ibrutinib plus rituximab compared to placebo plus rituximab.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.